Pain management therapies are evolving. Tramadol, a synthetic analogue to codeine first approved in 1995, has become a more common analgesic of choice.1

It has a rapid onset of action, is administered orally, and has been shown to be effective for a variety of moderate pain conditions, including postoperative abdominal surgery, arthroplasty recovery, active labor, and chronic noncancer pain (CNCP).2-5

Tramadol's common side effects—nausea, sweating, constipation—are well known to doctors. Yet a recent study raises concerns about the safety of the drug.

In July 2014, the Drug Enforcement Administration (DEA) officially redesignated tramadol from a non-classified drug to a schedule IV drug.6

Hypoglycemia and Tramadol

The most recent research links tramadol to fatal hypoglycemia, according to a new article in JAMA Internal Medicine.7

After analyzing hundreds of thousands of hospitalization records gleaned from the United Kingdom Clinical Practice Research Datalink, a team of Canadian researchers discovered 1,105 cases where patients were hospitalized for hypoglycemia—10% of them died.

Compared to codeine users, the patients taking tramadol were 52% more likely to be hospitalized with hypoglycemia. In secondary analyses, the results held up against an extensive scrutiny for confounding factors. "To our knowledge, this is the first epidemiological study investigating the association between tramadol use and hospitalization for hypoglycemia," the study said.

"While this is the more severe form (of hypoglycemia), it is possible that tramadol may increase the risk of the milder forms, which would have not been captured in our study. Therefore, the number of hypoglycemic events occurring with tramadol is likely to be much larger," Dr. Azoulay said.

The study also found the most acute risk of hypoglycemia was in the first 39 days of tramadol treatment. Because of this, Dr. Azoulay said monitoring patients during this time is a "sensible approach." He elaborated, "It would also be wise to educate patients on how to recognize early symptoms of hypoglycemia and steps to prevent the more harmful consequences."

In a separate study, Dr. Azoulay and colleagues found tramadol treatment was associated with a 2-fold increased risk of hyponatremia hospitalization, as well as a 3-fold increased risk within a restricted sub-cohort – the control being codeine.8

Safety Concerns

"Tramadol has been assumed to be relatively safe compared to other pain relievers. Since its beneficial effects on pain are limited, its use should be cautiously considered," Lewis S. Nelson, MD, professor of Emergency Medicine at the New York University School of Medicine in New York, told Practical Pain Management.

Previous studies have found that tramadol's metabolism to be highly erratic due to the dependent nature of the drug's pharmokinetics with the variable enzyme CYP2D6, wrote Dr. Nelson in a commentary accompanying the JAMA article.9

Drug-Drug Interactions

Tramadol may react dangerously to other drugs, as well. An elderly woman suffered dangerous bleeding a few days after combining tramadol with warfarin, a blood thinner.10 Xenobiotics like propranolol and nicotine may alter tramadol's effects,11 and serotonin syndrome has been reported in patients combining tramadol with antidepressants.9 Other practitioners advise caution, particularly when combining tramadol with other serotonergic agents.12,13

Risk vs Benefits

"As with all opioids, [tramadol] binds to the mu receptor, but it also increases serotonin levels. This latter mechanism opens the door to other potential adverse events, several of which have been reported with certain antidepressants [such as SSRIs]," Dr. Azoulay said.

"All drugs have risks and benefits," he added. "Thus, while our studies have identified adverse [effects] associated with tramadol, it is also important to consider many of its benefits, although those have been challenged by some."

One supposed benefit has been tramadol's ability to reduce morphine doses after surgery (morphine-sparing), the "holy grail of analgesia," noted Dr. Nelson. Unfortunately, the evidence of such a benefit is unremarkable so far.14

"Many drugs make this claim but none have been proven to be effective at significantly and consistently reducing the amount of an opioid needed to provide pain relief. Given the known and newly-discovered risks of tramadol, it does appear that clinicians should reevaluate how pain medications are combined, and in particular how opioid analgesics are used," Dr. Nelson said.

Dr. Azoulay's study into the association between tramadol use and hypoglycemia hospitalization was funded in part through research grants from the Canadian Institutes of Health Research and Canada Foundation for Innovation. Study coauthor Sammy Suissa, PhD, is the recipient of the James McGill Chair. None of the study's authors reported any conflicts of interest. There were also no conflicts of interest reported by the study's commentary authors, Dr. Nelson and David N. Juurlink, MD, PhD.

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